Psychedelics, as a plant-derived material, have been used for millennia in religious and medical practices. They produce an altered state of consciousness characterized by distortions of perception, hallucinations, dissolution of self boundaries and the experience of unity with the world. Classic psychedelics, also known as serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and psilocybin were extensively investigated in substance-assisted psychotherapy during the 1950s–1960s. These early clinical studies reported improvement rates in patients with various forms of depression, anxiety disorders, alcohol dependence. The development of modern neuroimaging techniques renewed interest in the investigation of psychedelics as a class of drugs that may reopen multiple therapeutic benefits. Current behavioral and neurochemical data show that psychedelics induce their psychological effects primarily via 5-hydroxytryptamine type 2A (5-HT2A) receptor activation and modulate neural circuits involved in mood and affective disorders. Clinical trials examining psilocybin have suggested that the compound relieves symptoms of depression and anxiety with rapid onset and longer duration. Serotonergic psychedelics enhance expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) as well as expression of genes associated with synaptic plasticity and stimulate synapse formation. These effects are similar to those produced by fast-acting antidepressant ketamine. Basic science research can reveal the neural mechanism of psychedelics action and how they can be used for treatment.